This proposal is to renew a collaborative grant application which includes Dr. Sartor at the University of North Carolina at Chapel Hill and Dr. Sue Tonkonogy at the College of Veterinary Medicine, North Carolina State University. The etiology of the inflammatory bowel diseases (1BD) is unknown, but both genetic and environmental factors are involved. In the current funding period of this grant we have used genetically engineered murine models to provide convincing evidence that the normal endogenous enteric bacterial flora are essential to the development of chronic colitis, in genetically susceptible rodents. Very importantly, we have demonstrated that all resident enteric bacteria are not equal in their capacities to induce inflammation: some are aggressive (Enterococcus faecalis in IL-10 KO mice), some are neutral (H. hepaticus in IL-10 -/- mice) and some are protective (Lactobacillus plantarum in IL-10 -/- mice). Chronic intestinal inflammation in these models is mediated by activated TH1 lymphocytes which are induced by normal cecal bacteria. We have demonstrated an important role for endogenous IL-10 in downregulating pathogenic responses of antigen presenting cells (APC) and T lymphocyte to normal bacterial components. Our data support the hypothesis that chronic intestinal inflammation in genetically susceptible hosts is the result of an overly aggressive cellular immune response to a subset of ubiquitous luminal bacterial constituents. Genetic susceptibility is determined by defective downregulation of inflammatory responses or defective mucosal barrier function. This clinically relevant hypothesis will be addressed by the following Specific Aims: 1. Determine the mechanisms by which endogenous IL-10 regulates responses of APC to environmentally relevant bacterial constituents and inflammatory mediators; 2) Determine the role of endogenous IL-10 produced by APC in regulating responses of naive and activated T cells to environmentally relevant bacterial antigens; 3) Identify the bacterial species preferentially inducing colitis and pathogenic immune responses in IL-10 deficient mice and protective responses in normal mice. The NIH-funded Core Center for Gastrointestinal Biology and Disease at UNC supports a barrier-intact gnotobiotic rodent facility, allowing the investigators a unique environment to selectively colonize germ-free mice with defined luminal bacterial species. These studies will provide novel insights into the pathogenesis of IBD and open new opportunities for novel therapeutic interventions designed to block induction of the antigen-specific immune response to luminal bacteria.